1. Field of the Invention
This invention relates generally to a surfactant polymer that comprises both non-thrombogenic and antimicrobial properties. More specifically, this invention relates to a surfactant polymer comprising a polymeric backbone of repeating monomeric units having functional groups for coupling with side chains, a plurality of hydrophobic side chains linked to the backbone via the functional groups, and a peptide based antimicrobial component linked to the backbone via the hydrophilic side chain. The antimicrobial surfactant may be applied to a surface of a medical device to impart the surfactant's non-thrombogenic and antimicrobial properties to the medical device surface.
2. Prior Art
The use of synthetic biomaterials to sustain, augment, or completely replace diseased human organs has increased tremendously over the past thirty years. Synthetic biomaterials are used in synthetic implants such as vascular grafts, heart valves, catheters and ventricular assist devices that have cardiovascular applications. Synthetic biomaterials are also used in extracorporeal systems and a wide range of invasive treatment, therapy delivery, and diagnostic systems. Unfortunately, existing biomaterials, suffer from well-known problems associated with surface-induced thrombosis or clot formation, such as thrombotic occlusion, thromboemboli, and infection.
Although the rate of infection is relatively low, the sheer volume of medical devices accounts for a large number of infections. For instance, for orthopedic implants, it has been reported that from the approximately 800,000 annually implanted devices in Europe, at least 1.5%, i.e., 12,000, peri-prosthetic infections will occur. Another device that has been associated with a high number of bloodstream infections is the central venous catheter. It is estimated that in the United States alone, at least 80,000 catheter related bloodstream infections (CRBSI) occur annually in intensive care units. Reports indicate that these CRBSIs are associated with as many as 24,000 patient deaths and increased health care costs ranging from approximately $10,000 to $30,000 per incidence. In many cases, the mean hospital stay is prolonged by at least 12 days, putting a heavy burden on the health care system as well as on patients and their families.
Besides infections, implanted medical devices may trigger a variety of other reactions, including inflammation, fibrosis and thrombosis. Undesired tissue responses can occur such as implant-associated protein adsorption and conformational changes which have been shown to promote blood coagulation and immune reactions. As a result, research efforts have been directed to reduce protein adsorption and cell interactions which subsequently improve biocompatibility.
One of the issues associated with catheters is thrombus formation on the surface of these devices. For example, central venous catheters (CVCs) are commonly used in blood and other bodily fluid exposed clinical practices. One of the foremost complications associated with their use is the potential for symptomatic or asymptomatic thrombosis. CVC thrombosis, in turn, may not only result in vascular and catheter occlusion but also infection, pulmonary embolism, and formation of right heart thromboemboli. Thrombi within cardiac chambers are associated with an increased risk of mortality due to their potential for embolization to the pulmonary vasculature. CVC thrombosis may also result in thrombo embolism of major organs. Estimates of CVC-related thrombosis vary depending on the site of insertion. For example, the incidence of thrombosis resulting from a peripherally inserted central catheter (PICC), in general, ranges from about 2% to about 4%. Pulmonary embolism is known to occur in approximately 15% of individuals with CVC related upper extremity deep vein thrombosis.
There have been several attempts to create nonthrombogenic surfaces on synthetic implants thereby increasing the blood-biocompatibility of implants. Early attempts included precoating the implants with proteins not involved in thrombosis, such as albumin, to mask the thrombogenic surface of the implant. However, such implants lose their non-thrombogenic properties within a short time. Attempts have been made to mask the thrombogenic surface by coating gelatin onto implants such as ventricular assist devices. While the gelatin coating reduced the thrombus formation, it did not adhere to the implant and it did not prevent thromboemboli and infection.
Attempts have also been made to render implants non-thrombogenic by coating the surface of the implant with polyethylene oxide to mask the thrombogenic surface of the implant. At times, this treatment has been known to reduce protein adsorption and thrombogenesis. However, the coupling of polyethylene glycol to the surface of the implant involves complex chemical immobilization procedures. Moreover, the coated implants do not consistently exhibit protein resistance because of the lack of control over the density of immobilized polyethylene oxide.
In addition, there have been many attempts to prepare non-thrombogenic surfaces by attaching anticoagulants such as heparin to biomaterials. However, each method requires complex immobilization procedures such that the implant surface is first modified by attachment of a coupling molecule before heparin can be attached. For example, the positively charged coupling agent tridodecylmethylammonium chloride (TDMAC) is coated onto an implant, which provides a positively charged surface and allows heparin, which has a high negative charge density, to be attached. However, the heparin slowly dissociates from the surface, to expose the positively charged TDMAC surface, which is particularly thrombogenic. Thus, the TDMAC heparin coated implant is successful only for short term implants such as catheters.
Furthermore, there have been many attempts to develop antimicrobial coatings. Among them are silver ion and antibiotic agent eluting mechanized coatings. These coating comprise either an antibiotic agent or have been impregnated with silver ions. These coatings are designed such that the antibiotic agent or the silver ions are released from the host coating material over a period of time.
Silver ion eluting coatings generally provide antimicrobial properties to a surface of a medical device. However, these coatings are known to increase thrombogeriicity of a surface and thus, could promote the formation of blood clots within the body. In addition, there has been concern about the potential negative side effects attributed to the elution of silver ions within the body.
Likewise, there is concern that microorganisms, such as bacteria, might become resistant to the antibiotic agent, thus reducing the effectiveness of such antibiotic eluting coatings. In addition, continued use of these antibiotic agents could, over time, promote the mutation of antibiotic resistant microorganisms, such as bacteria. Antibiotic eluting coatings are also constrained by the volume of the antibiotic agent therewithin. Therefore, once the antibiotic agent is exhausted from the host coating material, the antimicrobial properties of the coating are greatly diminished.
Antimicrobial peptides, on the other hand, naturally reside within many living organisms and are known to be generally biocompatible. Unlike anti-biotic and silver ion eluting coatings of the prior art, the present invention comprises a surfactant material within which the antimicrobial peptide resides within a localized area of the coating material and is not eluted further throughout the body.
The antimicrobial properties of these peptides result from the peptide's ability to disrupt the cell membrane of various bacteria. When an antimicrobial peptide comes into contact with a bacterial microorganism, the peptide renders the bacteria's cell membrane permeable, thus disrupting the cell structure such that the bacteria microorganism expires.
Despite these considerable research efforts, synthetic biomaterials, and medical devices made from such biomaterials, still suffer well-known problems associated with bacteria surface-induced thrombosis and bacterial infection. Accordingly, it is desirable to have new materials that can be used to coat biomaterials and to change their surface properties such that they are less likely to promote thrombogenicity and infection within the human body.